Process for preparing allylic rearrangement compounds of antibiotics sf-837 and sf-837a2

ABSTRACT

THE ALLYLIC REARRANGEMENT PRODUCTS OF ANTIBIOTICS SF-837 AND SF-837A2 ARE OBTAINED BY AN ACID CATALYZED REACTION WHEREIN AN OH GROUP IS SHIFTED FROM THE 9 TO THE 13 POSITION IN AQUEOUS SOLUTION.

United States Patent Oifice Patented Oct. 23, 1973 3 767 641 For comparing known macrolide antibiotics the present a substance is easily crystallized from conventional organic ;%g gg K{ solvents without a complicated separating procedure and OTICS SI -837 AND SF 837A therefore, a pure product can be easily obtained, which Takashi Tsuruoka, Kawasaki, Shunzo Fukatsu and Bunzo 5 is considered to be PaYtiCl1 1af1y Suitabl? as an injection Nomiya, Tokyo, and Shigeharu Inoue and Taro Niida, preparation. Furthermore, it may readily be understood Yokohama, Japan, assignors to Meiji Seika Kaisha, that the allylic rearrangement compounds of the present Ltd., Tokyo, Japan invention may be used not only in their isolated form, but

No Draw g- Filed 1971, 193,180 also in the form of a mixture of two or more of them for Claims priority, application Japan, Oct. 27, 1970,

45/93 992 therapeutic purposes. Int CL C07c 129/18 SF-837 and SF-837A substances are novel macrolide .s 2 0 210 AB 3 Claims antibiotics obtained from a culture liquid of a Streptomyces strain, Which is named Streptomyces micarofaci- ABSTRACT OF THE DISCLOSURE ence nov. sp. This strain has been deposited in unrestricted form in the ATCC under AT CC No. 21454, by the present inventors (US. patent application No. 3,809 filed Jan. 19, 1970). The antibiotics SF-837 and SF-837A are useful in the medical treatment of Gram-positive bacterial infections and have the following chemical Structural For- The allylic rearrangement products of antibiotics SF-837 and SF-837A are obtained by an acid catalyzed reaction wherein an OH group is shifted from the 9 to the 13 position in aqueous solution.

2O mula Ia:

OH H3 0 I OH 3 BACKGROUND OF THE INVENTION wherein, in SF-837, R is -COCH CH and R is Field of the invention COCH2CH3, and, 111 SF-837A2, R1 18 C0CH2OH3 and R --COCH CH CH The present invention relates to a process for preparing novel derivatives of antibiotics SF837 and SF837A SUMMARY OF THE INVENTION that is, novel antibiotics derived by acting an appropriate catalyst on an Original substance to an allylic The present inventors have found that, when subjecting rearrangement. the above SF837 and SF-837A substances to an acidic i i of h prior t condition in solution, an isomerization reaction resulting For therapeutic purposes, the free bases, the acid in an rearrangement of the hydroxyl group from 9-position addition Salts and the allylic rearrangement compounds of lactone ring in the Formula Ia to the 13-position takes of antibiotics SF-837, SF837A substances of the present Place to Produce the novel allylic rearrangement 00minvention may conventionally be formulated into tablet pounds of SF-837 and SF-837A represented by the or capsule form for oral administration and into aqueous Formula Ib:

mycarose herein in the allylic rearrangement compound of the solutions or suspensions for in ection, with or without W pharmaceutically acceptable additives, such as a carrier, SF 837 substance R1 15 COCHZCHa and R2 is vehicle, suspension agent and the like. COCH CH 3 4 and, in the allylic rearrangement compound of the TABLE 1 SF-837A substance, R is COCH CH and R is -COCH CH C-H Both of the allylic rearrangement Reaction condition Percent compounds of SF837 and SF-837A are novel sub- T 113 1 1 rn irne, stances 5 pH 6 days Ia Ib product Therefore, the present invention is a process for pre- 2 paring an allylic rearrangement compound of SF-837 or 3:8 5 3i; 12 SF-837A characterized by acting an acid catalyst on 3.0 15 2 76 3 gig antibiotics SF-837 or SF-837A in a solution and subse- 2:8 30 3 i; 30 30 quently collecting the resulting allylic rearrangement com- 10 3. 0 5 12 g 312 pound of SF-837 or SF-837A from the reaction mixture. 3:8 50 23 Z The rearrangement from the Compound Ia to the Com- 3. 0 so 2 20 is e 76 pound Ib is one kind of equilibrium reaction and the ratio Hours of Ia to Ib is about 6 to 4 under the most favorable con- 2 Minutes dtion. 15 DETAILED DESCRiPTION OF THE INVENTION In the allylic rearrangement reaction, the presenceof water is indispensable. The allylic rearrangement reaction AS Show m Formula 812L837 and sF-837A2 was not observed in an absolute organic solvent of acestarices are I of a 16 member cyclolacmne m6 tone, chloroform, benzene, ethylacetate, ethylether, diox- Sugar mycammose and i neutral mycarose 20 ane, tetrahydrofurane, toluene, etc. The present reaction a m the case where the PH 18 too dunng the proceeds in a water-containing solvent, and, as an organic substanies are decomposed 811196 a hydrPlYss solvent in this case, ethanol, acetone, dioxane and tetrareaction occurs with respect to the glycoside bond 111 the hydrofuran are usually used which are miscible with mycarose {nolety Preferennauy to the anyhc h Water. The water content is desirably above 50% in pracmeht h on the other hand: when the PH 15 ah'ave tice, although the reaction is observed if it is above 5%. the anyhc reaFrangement does not f Plac? When the reaction is completed the reaction product e h the operable pH In the reaction of thls (allylic rearrangement compounds) and the unreacted invention is within the range of 1 to 4, and most favorably, raw materials exist as an acid salt, and, in order to 2 to arate the reaction product from the mixture, it is most ef- As an fi for catalyzmg i presentfeaqtlofl any,acld ficient to utilize such a method as converting the both macan be h regardless, phase 1 hqmd Solid or terial to the respective free bases and utilizing the dif- Provlded that,the acld gives h of 1 ference of the both free bases in solubility for benzene. and 1S Stabl? men under, h I That is, such a difference in solubility properties exist that hydrochlfmc pkfosphPnc pydrqlodlc acld the free base of the ailylic rearrangement compound is drobromlc acetlc a P f acid slightly soluble While the free base of unreacted raw maacetic acid, trichloroacetic acid, trifiuoro acetic acid, tarmrial is easily Soluble. taric acid, oxalic acid, malonic acid, maleic acid, citric The anylic rearrangement compound is much better in acid paratoluf'ne Sulfunc acid niethasulfomc crystallization than the unreacted raw material, and, in may be used m the Present Ramon 40 case of existing in pure form, it can be easily crystallized Althougil the reaction temperature depends upon the out from even a solvent, other than benzene, i.e., from concentration of the acid, the operable temperature ranges even methanol, ethanol chloroform em However, in 2 to 80 g i g g i such an impure state of mixture with unreacted material, g i to th n 3 the object cannot be attained with use of these solvents, t reachtm temperahure e 5 e but it is most eifective to use benzene. That is, when, at the amen i 1f thfi reaction tfimperamre lower time the reaction is completed, the reaction mixture is adi g g tune g i exended 16 justed to the alkaline side, i.e., 7 to 9 in pH, and is shaken Z 8 g: a 3 1 con 2, with an organic solvent, such as ethylacetate, chloroform, i i g r ethylether, etc., the reaction product and unreacted raw e eac 1 p e Sn e S 15 C O y I 1 15 a material are transferred to the organic solvent layer in the degree as to prevent the reaction solvent from evaporating form of the free base Benzene can be utilized in this and commonly the reaction 18 carried out at atmospheric extraction, although it is inferior to the former in extrac pressure tion ratio. The pH during extraction may preferably be TABLE 1 above 6; howeve, if the pH is higher, a deacylation reac- Percent f tion takes place. Consequently, a pI -I of above 6 should be Reactmh condition D avoided. The residue is treated with a small amount of T 1 Time, ifgfi; benzene. The synthetic raw materials, S F-837 and SF- PH hm Product 837A are dissolved and the desired allylic rearrangement 55 1 0 0 100 compound is separated as an insoluble portion. Then, g-g g i Z? g2 when the benzene insoluble portion is filtered and crystalafo 55 4 35 5 m lized from benzene or acetone, the allylic rearrangement 2- g 38 g 3 compounds of SF-837 and SF-837A are obtained as N Th white needle crystals. The physical and chemical proper- 0TE. e above values were calculated irorn the results obtained b separating the reaction material into Ia and Th by a silica gel thin iaye r nes of tha auyhc rearrangemeint compounds of SF chromatography and thereafter coloring them with sulfuric acid and 5 and SF837A2 of the Present Invention are as Shown in measuring with a densitometer. bl 3 TABLE 3 Allylie rearrangement Allylie rearrangement. compound of SF-837 compound of SF-837A2 Appearance White needles White needles. Melting point.--" 205-210" C 203207 C. Elemental analysis.. 0 60.38, H 8.73, N 1.70% C 60.68,]111. 62, N 1.63%. Molecular woir ht 813. 827. Molecular formula CnHarOisN C42HGQOX5N- Ultraviolet absorption 234111;: (El u 1.340) Figure 1-. 23 i mp (E i m.330) Figure 2: Intrared absorptiom Figure 3 Figure 4.

Optical rotation [01]) -57 (C=1, ethan0l) [cla -56 C. (C=1, ethanol).

Allylic rearrangement compounds of SF-837 and SF- 837A inhibit the growth of staphylococcus and other Gram positive bacteria in vitro and exhibit the same inhibitory action towards staphylococci having a resistance against streptomycin, actinomycin, kanamycin, penicillin and tetracycline as to the bacteria sensitive strains. Their antibacterial spectrum is shown in Table 4.

TABLE 4 Minimum inhibitory concentration (mcg./ml.) allylic rearrangement compound oi- Test micro-organisms SF- 837 SF-837A2 Staphylococcus aureaus 2091 0. 39 0.39 Staphylococcus aurcaus resistant to (penicillin)- 0. 39 0. 39 Staphylococcus aureaus resistant to (streptomycin and A-249 substance) 0. 39 0. 39 Staphylococcus aureaus resistant to (novobiocin) 12. 5 5 Staphylococcus aureaus resistant to (kanamycin) 1. 56 0. 78 Staphylococcus aurcus Smith 0. 09 0. 09 Staphylococcus aurcus Terajim 0.78 0.39 Staphylococcus aureaus resistant mycin-tetracycline penicillin) 0.78 0.39 Bacillus subtilis ATCC 6633...- 0. 19 0. 09 Sarciua lutea 0.05 0.05 M ycobacteriu'm smepmatis 607. 25. 12. Escherichia coli 25. 0 25. 0 Pseudo'mo'nas acrugiizosa 25. 0 25. 0

Medium: Bouillon, but glycerine bouillon for Mycobacterium. Further, allylic rearrangement compounds of SF-837 and SF-837A exhibited an excellent therapeutic effect in an experimental animal infected with a staphylococcal infection. That is, the experimental results for oral administration for mice was as follows:

In the oral administration of 6 g./kg. of the allylic rearrangement compound no deaths to the mice employed was observed. Thus, it should be noted that allylic rearrangement compounds of SF-837 and SF-837A are lower in toxicity and exhibit a more excellent etfect in the treatment of staphylococcus infections than the original substances and kitasamycin.

Furthermore since the allylic rearrangement com pounds of SF-837 and SF837A are obtained in pure form without a complicated separatory procedure, it is possible to use these compounds in a preparation for parental use.

The present invention will be further illustrated by the following example, which are merely intended to be illustrative and not limitative of the present invention.

EXAMPLE 1 One gram of SF-837 substance was dissolved in hydrochloric acidic water (adjusted to pH 3.0) and heated at 55 C. for 4 hours. The reaction liquid was adjusted to a pH of 8.0 with sodium hydroxide and extracted with 50 ml. of ethyl acetate. The ethyl acetate layer was evaporated to dryness under reduced pressure and dissolved in 5 ml. of benzene. The benzene insoluble portion was filtered, dissolved in 4 ml. of acetone and allowed to stand at 5 C. to deposit crystals. The crystals were filtered and dried in a desiccator to obtain 280 mg. of white needle crystals of the allylic rearrangement compound of SF-837.

The result of the experiment carried out with inorganic acids, other than hydrochloric acid under similar conditions is shown in the following table:

Five hundred milligrams of SF-837A was dissolved in 30 ml. of 0.1 M acetic acid (pH 2.8) and reacted at 50 C. for 3 hours. After neutralization, the reaction liquid was extracted with 30 ml. of chloroform. The solvent layer was concentrated and dried and treated with 3 ml. of benzene t0 filter the insoluble portion. This portion was dissolved in 10 ml. of hot benzene and allowed to stand at room temperature to deposit crystals. The crystals were dried in a desiccator to obtain mg. of white needle crystals of the allylic rearrangement compound of SF837A The result of this experiment carried out with organic acids, other than acetic acid under similar conditions is shown in the following table:

TABLE 7 Reaction condition Temp, Time, Yield, Organic acid pH 0. hours percent Propionic acid 3. 8 60 6 21 Monochloro acetic acid 2.8 52 3. 5 23 Trichloro acetic acid- 3.0 55 4. O 24 Trifluoro acetic acid 2. 5 48 3. 5 23 Tartaric acid 3. 2 50 4 27 Oxalic acid 2. 8 50 4. 5 20 Malonic acid. 3. 2 55 4. 0 25 Maleic acid 3. 5 60 4. 5 26 Citric acid 2. 8 52 4. 0 18 Paratoluene sulfoni 2. 5 48 5. 0 16 Methasulfuric acid. 3. 0 55 4.0 22

EXAMPLE 3 Two grams of SF-837 was dissolved in 50 ml. of a 50% aqueous acetone solution and adjusted to a pH of 3 with sulfuric acid, and reacted at 40 C. for 8 hours. After neutralization, the reaction liquid was .distilled out acetone under reduced pressure and extracted with 30 ml. of ethyl acetate. The ethyl acetate layer was concentrated under reduced pressure and the residue was dissolved in 8 ml. of benzene. The insoluble portion was dissolved in 10 m1. of acetone and allowed to stand at 5 C. to deposit crystals. The crystals were dried to obtain 500 mg. of white needle crystals of the allylic rearrangement compound of SF-837.

The result of this experiment carried out under other conditions is shown in the following table:

TABLE 8 Reaction condition Tem Time Yield Solvent system pH hours percent Acetone-water:

8:1 3.0 (hydrochloric 50 6 5 acid).

4 1 -.do 50 6 l2 1:2 do 5o 6 27 Dioxane-waterz .5 (sulfuric acid). 60 4. 5 22 Although the present invention has been adequately described in the foregoing specification and examples included therein, it is readily apparent that various changes and modifications can be made without departing from the scope and spirit thereof.

What is claimed is:

1. A process for preparing the allylic rearrangement compounds of a member selected from the group consisting of antibiotics SF-837 and SF-837A2, which comprises the following stepwise procedure:

(1) subjecting antibiotics SF-837 or SF-837A con- .tained in a member selected from the group consisting of water and a water-containing organic solvent to acid catalysis, and

(2) subsequently, recovering the allylic rearrangement compound of antibiotic SF-837 or antibiotic SF 837A; from the reaction mixture,

said acid catalysis taking place in the presence of an acid pH.

2. The process of claim 1, wherein said pH ranges from 1 to 4.

3. The process of claim 1, wherein said pH ranges from 2.0-3.5.

4. The process of claim 1, wherein said acid catalysis is produced by an acid selected from the group consisting of HCl, H PO HI, HBr, CH COOH, CH CH COOH,

8 CH ClCOOl-l, CCI COOH, CF COOH, tartaric acid, oxalic acid, malonic acid, maleic acid, citric acid, p-toluene sulfuric acid, and metha-sulfonic acid.

5. The process of claim 1, wherein said process takes place at a temperature ranging from 10 to C.

6. The process of claim 3, wherein said process takes place at a temperature of from 15 to 50 C.

7. The process of claim 1, wherein said procms takes place at a pH of 3.0, a temperature of 50 C. and for a time of 4.0 hours.

8. The process of claim 1, wherein said water-containing organic solvent is a member selected from the group consisting of ethanol, acetone, dioxane, and tetrahydrofuran.

References Cited UNITED STATES PATENTS 3,535,309 10/1970 Hata et a1 260-410 AB LEWIS GOTTS, Primary Examiner I. R. BROWN, Assistant Examiner US. Cl. X.R. 424- 

